Vaccination constitutes the most cost-effective tool for the prophylaxis of infectious diseases.
The elicitation of an efficient immune response at the mucosal level after immunization is highly desired. Among the approaches for triggering an efficient immune response, the use of attenuated enteropathogenic bacteria as carriers has received substantial attention. Attenuated strains of bacteria constructed by recombinant DNA technology have been developed as live vaccines for humans and other animals. For a recent review of the use of attenuated bacterial strains as antigen delivery vectors, see Medina and Guzman, Vaccine 19:1573-1580 (2001), which is hereby incorporated by reference along with the references cited therein. Examples of attenuated bacteria that have been successfully used as antigen delivery vectors include Listeria monocytogenes, Salmonella spp., Vibrio cholera, Shigella spp., Mycobacterium bovis BCG, Yersinia enterocolitica, Bacillus anthracis, Streptococcus gordonii, Lactobaccillus spp., Staphylococcus spp. and E. coli. Id. Such attenuated bacteria can stimulate mucosal and/or systemic immunity against the carrier itself or against heterologous antigens expressed by the carrier bacteria. See also, e.g., U.S. Pat. Nos. 6,024,961; 4,888,170; 5,389,368; 5,855,879; 5,855,880; 5,294,441; 5,468,485; 5,387,744; 5,840,483; 5,672,345; 5,424,065; 5,888,799; 5,656,488; 5,006,335; 5,643,771; 5,980,907; 5,851,519 and 5,527,529, describing attenuated bacterial strains suitable for use as vaccines, all of which are hereby incorporated by reference. Th1 and Th2 cells exist in humans and other animals. Th1 cells are the principal regulators of type 1 immunity, while Th2 cells stimulate high titers of antibody. Clinically, a correlation has been established between antibody titer and efficacy of vaccines. Thus, a Th2 dominant immune response is highly desirable for certain vaccine applications. Achieving the correct balance between the different arms of the immune system when an immune response is elicited is an important factor bearing on the efficacy of a particular vaccine. Golding and Scott, 1995 Ann NY Acad Sci, 754:126-137, Del Prete, B., 1992, Allergy, 47:450-455, Dong and Flavell, 2000, Arthritis Res, 2:179-188 and Spellberg and Edwards, 2001, Clin Infect Dis, 32:76-102 present recent reviews on Th1 and Th2 mediated immune responses.
Many factors have been shown to effect the polarization of Th0 cells into mature Th1 or Th2 cells. For example, the local cytokine environment, the presence of immunologically active hormones, the dose and route of antigen administration, and the type and characteristics of the antigen-presenting cell stimulating the T cell all can have an effect on the balance of Th1 versus Th2 type immune response that is elicited. Thus, it is conceivable that the immune response can be modulated by manipulating any one, or combination of these factors.
One area that has received considerable attention is altering the characteristics of the antigen presenting cell, or antigen carrier, in order to modulate the type of immune response elicited. Several studies have investigated the immune responses to heterologous antigens elicited by carrier bacteria strains that harbor mutations in various genes. Dunstan et al., 1998, Infect and Immun, 66:732-740; Medina et al., 1999, Infect and Immun, 67:1093-1099; VanCott et al., 1998, Nature Medicine, 4:1247-1252; Pascual et al., 1999, Infect and Immun, 67:6249-6256. The studies above confirm that different attenuating mutations and combinations of mutations are capable of eliciting immune responses with a differing balance of Th1 versus Th2 levels.
There remains a need for further research in the development of strategies to target appropriate helper T cell responses according to particular needs. Thus, the availability of carrier strains that are well characterized in terms of the particular immune response they elicit should enable fine tuning of the immune response triggered against heterologous or homologous antigens according to specific needs.
Related Art:
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